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Title: SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models
Authors: Quinti, L
Casale, M
Moniot, S
Pais, TF
Van Kanegan, MJ
Kaltenbach, LS
Pallos, J
Lim, RG
Naidu, SD
Runne, H
Meisel, L
Rauf, NA
Leyfer, D
Maxwell, MM
Saiah, E
Landers, JE
Luthi-Carter, R
Abagyan, R
Dinkova-Kostova, AT
Steegborn, C
Marsh, JL
Lo, DC
Thompson, LM
Kazantsev, AG
First Published: 14-Jul-2016
Publisher: Elsevier
Citation: Cell Chem Biol, 2016, 23 (7), pp. 849-861
Abstract: There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders.
DOI Link: 10.1016/j.chembiol.2016.05.015
eISSN: 2451-9456
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2016 Elsevier Ltd. This version of the paper is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Appears in Collections:Published Articles, Dept. of Neuroscience, Psychology and Behaviour

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